Pain afflicts well over 60 percent of cancer patients, and in 36 percent it is severe enough to limit patient's ability to function. Despite worldwide efforts to improve management of pain related to cancer and other persistent pain syndromes, pain is often inadequately treated. Research on analgesic therapy has largely ignored gender-related differences in pain physiology, even though such differences have been demonstrated in animals and humans. Women have lower pain detection and tolerance thresholds, and pain sensitivity appears to fluctuate with hormone changes during the menstrual cycle, all of which may affect analgesic response to drug treatment. Moreover, side effects often limit the efficacy of opioid analgesics. Recent data from this laboratory suggest that women suffer more opioid- mediated side effects compared to men, and could limit their ability to receive adequate analgesia. Also, sex hormones that are known to affect cognitive function may modulate opioid-side effects at different times during the menstrual cycle. Hence, it is crucial to identify between-gender differences in both the analgesic and side effects of opioids in order to optimize treatment strategies that offer continuous pain control and minimal side effects. This application describes a pharmacodynamic study on the muopioid - morphine (part 1) and the kappa-opioid -butorphanol (part 2) in healthy volunteers, using well-validated experimental pain methodologies and robust psychometric assessments tools, coupled with a phamacokinetically-tailored IV infusion technique that is capable of producing and sustaining target opioid concentrations in plasma. The primary aims are to determine 1) whether mu- and kappa-opioid mediated analgesia and side effects differ between women and men, 2) whether opioid-mediated side effects vary with menstrual phase. In each part of the study, 18 women and 18 men will receive sustained opioid infusions; the women will be assessed at the peri-menses, follicular, and luteal phases of the menstrual cycle (confirmed by hormone assays), and the men will be assessed on two separate occasions. At each study session, we will administer repeated trials of pain testing, assessments of subjective effects, cognitive and psychomotor performance, respiratory drive, and pupilometry; i.e., before, during and following opioid infusion. Pain testing will consist of subjective ratings of electrical and thermal stimuli, as well as assessment of temporal summation as an indicator of central hypersensitivity. As a secondary aim, opioid infusions will be targeted to achieve equi-analgesic levels of morphine and butorphanol such that the analgesia-to-side effect ratio of these two opioids can be compared.